The genetics behind colon cancer is now well described, but even among tumors with identical genetic mutations, tumor heterogeneity remains problematic in the clinical setting. Epigenomics, including histone post- translational modifications (PTMs), can modulate gene expression and explain heterogeneity. Epigenomic regulators have gained attention as candidates for targeted cancer therapy. However, there are still large gaps in understanding the role of epigenomics in colon cancer. This proposal?s primary objective is to uncover the roles of KAT2A and KAT2B in normal intestinal epithelium homeostasis and colon cancer. These genes encode histone lysine acetyltransferase enzymes, whose functions have not yet been elucidated in colon cancer. KAT2A is normally expressed in intestinal stem and proliferative cells, while KAT2B is enriched in differentiated epithelium. In tumors, KAT2A levels are elevated, while KAT2B levels are reduced. I hypothesize that KAT2A catalyzes histone PTMs to promote proliferative gene expression and drive colon tumorigenesis, while KAT2B promotes differentiation gene expression and suppresses colon tumorigenesis. Alternatively, these lysine acetyltransferases could function redundantly. The rationale for this study is based on preliminary data showing that KAT2A and KAT2B are differentially expressed in normal versus cancerous colon tissue and the observation that they can catalyze histone acetyl as well as non-acetyl histone modifications. Importantly, these factors have not been functionally tested in vivo in the intestine.
Aim 1 will use novel genetic mouse models to assess the effects of KAT2A/KAT2B knockout on intestinal homeostasis and colon cancer by employing histology studies, organoid assays, tumor quantification, and qRT-PCR screening.
Aim 2 will use histone PTM mass spectrometry analysis, RNA-seq, and ChIP-seq to determine 1) important acetyl and non-acetyl histone PTMs catalyzed by KAT2A/KAT2B and 2) how the binding sites of KAT2A/KAT2B and their PTMs correlate with changes in the transcriptome. The significance of this proposal is that it will improve our understanding of epigenetic mechanisms in colon cancer and introduces two candidate genes, KAT2A and KAT2B, to target in colon cancer. With the training plan devised by Dr. Michael Verzi, the applying fellow will 1) gain expertise in genetics and cancer, 2) develop effective scientific communication skills, and 3) prepare to lead a lab as an independent translational cancer researcher within a nurturing, resourceful, and collaborative environment at Rutgers University.
Colorectal cancer is ranked as the second leading cause of cancer-related deaths for men and women combined. A promising new class of therapeutics targets epigenetic regulators, yet we do not currently know the functions of many genes in this class. My proposal seeks to define the role of untested epigenetic regulators in colon cancer.
